Targeted HAI-2 deletion causes excessive proteolysis with prolonged active prostasin and depletion of HAI-1 monomer in intestinal but not epidermal epithelial cells.

Mutations of SPINT2, the gene encoding the integral membrane, Kunitz-type serine inhibitor HAI-2, primarily affect the intestine, while sparing many other HAI-2-expressing tissues, causing sodium loss in patients with syndromic congenital sodium diarrhea. The membrane-bound serine protease prostasin was previously identified as a HAI-2 target protease in intestinal tissues but not in the skin. In both tissues, the highly related inhibitor HAI-1 is, however, the default inhibitor for prostasin and the type 2 transmembrane serine protease matriptase. This cell-type selective functional linkage may contribute to the organ-selective damage associated with SPINT 2 mutations. To this end, the impact of HAI-2 deletion on matriptase and prostasin proteolysis was, here, compared using Caco-2 human colorectal adenocarcinoma cells and HaCaT human keratinocytes. Greatly enhanced prostasin proteolytic activity with a prolonged half-life and significant depletion of HAI-1 monomer were observed with HAI-2 loss in Caco-2 cells but not HaCaT cells. The constitutive, high level prostasin zymogen activation observed in Caco-2 cells, but not in HaCaT cells, also contributes to the excessive prostasin proteolytic activity caused by HAI-2 loss. HAI-2 deletion also caused increased matriptase zymogen activation, likely as an indirect result of increased prostasin proteolysis. This increase in activated matriptase, however, only had a negligible role in depletion of HAI-1 monomer. Our study suggests that the constitutive, high level of prostasin zymogen activation and the cell-type selective functional relationship between HAI-2 and prostasin renders Caco-2 cells more susceptible than HaCaT cells to the loss of HAI-2, causing a severe imbalance favoring prostasin proteolysis.

The impact of COVID-19 epidemic on emergency department visits of older patients in Taiwan.

BACKGROUND: The number of emergency department (ED) visits has significantly declined since the COVID-19 pandemic. In Taiwan, an aged society, it is unknown whether older adults are accessing emergency care during the COVID-19 epidemic. Therefore, this study aimed to investigate the impact of COVID-19 on the ED visits and triage, admission, and intensive care unit (ICU) hospitalization of the geriatric population in a COVID-19-dedicated medical center throughout various periods of the epidemic. METHODS: A retrospective chart review of ED medical records from April 9 to August 31, 2021 were conducted, and demographic information was obtained from the hospital's computer database. The period was divided into pre-, early-, peak-, late-, and post-epidemic stages. For statistical analysis, one-way analysis of variance followed by multiple comparison tests (Bonferroni correction) were used. RESULTS: A statistically significant decrease in the total number of patients attending the ED was noted during the peak-, late-, and post-epidemic stages. In the post-epidemic stage, the number of older patients visiting ED was nearly to that of the pre-epidemic stage, indicating that older adults tend to seek care at the ED earlier than the general population. Throughout the entire epidemic period, there was no statistically significant reduction in the number of the triage 1& 2 patients seeking medical attention at the emergency department. In the entire duration of the epidemic, there was no observed reduction in the admission of elderly patients to our hospital or ICU through the ED. However, a statistically significant decrease was observed in the admission of the general population during the peak epidemic stage. CONCLUSIONS: During the peak of COVID-19 outbreak, the number of ED visits was significantly affected. However, it is noteworthy that as the epidemic was gradually controlled, the older patients resumed their ED visits earlier that the general population as indicated by the surge in their number. Additionally, in the patient group of triage 1& 2, which represents a true emergency, the number did not show a drastic change.

Owen, Sugaya, and Hayashida Classifications Give Poor Intra- and Inter-Rater Agreement on a Magnetic Resonance Imaging Evaluation of Subscapularis Tendon Retears.

PURPOSE: To investigate the intra- and inter-rater agreements for magnetic resonance imaging (MRI) evaluations of subscapularis tendon integrity at 6 months after arthroscopic rotator cuff repairs. METHODS: Patients who had isolated or combined subscapularis tears and had undergone arthroscopic rotator cuff repairs were retrospectively included. The exclusion criteria included revision of arthroscopic surgery, minor subscapularis tears without repair, and inadequate postoperative images. MRI scans 6 months after surgery were used for the purpose of accessing the integrity of the subscapularis tendons. Three orthopaedic surgeons blindly evaluated the images twice at 2-week intervals. Three currently available classifications were used: the Owen classification, the Sugaya classification, and the Hayashida classification. Dichotomization and trichotomization methods were used for the Sugaya classification and Hayashida classifications. The aforementioned classification scores were combined for the agreement evaluation. Intra- and inter-rater agreement was assessed by calculating the Fleiss' kappa coefficients. RESULTS: A total of 35 patients were included. Both the Owen and Hayashida classifications had poor inter-rater agreements (κ = 0.10 and 0.04, respectively) and poor-to-weak intra-rater agreements (κ = 0.27-0.44 and 0.16-0.45, respectively). The Sugaya classification had poor inter-rater agreement (κ = 0.10) and poor intra-rater agreements (κ = 0.16-0.32). Dichotomization and trichotomization of Sugaya and Hayashida classifications did not lead to superior agreements. The classification combination resulted in poor inter- and intra-rater agreements (κ = 0.01-0.12 and 0.08-0.39, respectively). CONCLUSIONS: The Owen classification, Sugaya classification, and Hayashida classification had poor intra- and inter-rater agreement in terms of evaluating subscapularis tendon re-tears on 6 months' postoperative MRI. The dichotomized and trichotomized classifications as well as the combined classifications from currently available classifications did not lead to superior agreements. LEVEL OF EVIDENCE: Level IV, diagnostic: case series.

Biomechanical comparisons of hook plate and screw fixations in split-type greater tuberosity fractures of the humerus.

BACKGROUND: Screws and plate are commonly utilized for the fixation of split-type humeral greater tuberosity (GT) fractures. However, the mechanical properties of these 2 types of fixation methods have not been compared directly. The aim of the present study was to evaluate the classic 2 screws fixation with hook locking plate from a mechanical perspective. METHODS: Sixteen synthetic humerii (Sawbones Pacific Research Laboratories, Vashon, WA, USA) were divided into 2 groups. An osteotomy was performed to simulate a split-type GT fracture. Group A (n = 8) was fixed with 2 standard parallel screws. Group B (n = 8) was fixed with a hook plate. Each specimen was tested with traction force at 45° shoulder abduction. Following the 20-N preload, a 500-cycle loading test was applied with a force ranging from 20 to 200 N (valley/peak), and the interfragmental displacement was measured periodically at intervals of 100 cycles. Finally, all the specimens were pulled with destructive force at a rate of 5 mm/min until catastrophic failure. RESULTS: The hook plate exhibited greater construct stiffness than the screw fixation (63.2 ± 6.1 N/mm vs. 40.9 ± 3.4 N/mm, P < .001). All of the specimens completed the entire cyclic loading test without catastrophic failure, and the fragment displacement after 500 cycles was 0.4 ± 0.2 mm for the hook plate and 2.1 ± 0.3 mm for screw fixation, which was statistically lower in the plate group (P < .001). In terms of failure load, the hook plate group exhibited a significantly greater value than the screw group (770.6 ± 94.6 vs. 427.5 ± 45.1 N/mm, P < .001). The failure modes of both fixation methods were distinct. CONCLUSION: In humeral GT fracture fixation, hook plate fixation appears to offer greater construct stiffness and failure load while maintaining fragment stability to resist a physiological traction force. The current study provides support from a mechanical perspective for the clinical application of the hook plate.

Post-Cholecystectomy Right Hepatic Artery Pseudoaneurysm Induced by Generalized Seizure: A Case Report.

Pseudoaneurysm is a rare complication of laparoscopic cholecystectomy (LC). In most cases, the patient presents with gastrointestinal bleeding or hemoperitoneum. Here, we present a case with a post-cholecystectomy right hepatic artery pseudoaneurysm (PSA) induced by a generalized seizure. A 39-year-old male was sent to the emergency room with a generalized seizure and a loss of consciousness for approximately 5 min. Diffuse abdominal pain was complained of after consciousness returned. The surgical history of LC 13 days prior was mentioned. Abdominal computer tomography (CT) revealed a lobulated fluid accumulation in the gallbladder fossa with prominent fatty stranding and suspected biloma formation. After admission for one week, sharp abdominal pain was observed. Abdominal CT angiography revealed a right hepatic artery pseudoaneurysm. Transcatheter arterial embolization was performed with a total of seven platinum coils. In conclusion, it is important for doctors to take pseudoaneurysm into consideration in the patient who presents with seizure attack after receiving LC. Late discovery of PSA when it is ruptured can lead to fatal conditions, such as severe hemoperitoneum.

Long-term oncologic result of laparoscopic versus open gastrectomy for gastric cancer: a propensity score matching analysis.

BACKGROUND: Laparoscopic gastrectomy is an acceptable procedure for early-stage gastric cancer; however, most patients are diagnosed at an advanced stage and older age in Taiwan. The feasibility and safety of applying laparoscopic gastrectomy in daily practice remain unclear. This study aimed to examine the short- and long-term outcomes of laparoscopic gastrectomy versus open procedures. METHODS: From 2007 to 2015, 192 patients who underwent open gastrectomy and 189 patients who underwent laparoscopic gastrectomy for gastric cancer at a single center were included. Propensity score matching analysis was used to adjust selection biases associated with age, preoperative hemoglobin, the extent of resection, tumor size, and stage of the disease. The demographics, perioperative parameters, short-term postoperative results, and 5-year survival data were analyzed. RESULTS: Open gastrectomy was more frequently performed in the elderly, larger tumor size, advanced stage of the disease, and disease requiring total gastrectomy or combined organ resection. After propensity score matching, 108 patients with laparoscopic gastrectomy were compared to 108 patients with open gastrectomy. The morbidity rates were not different in both groups (25.9%), while hospital stay was shorter in the laparoscopic group (16.0 vs. 18.8 days, p = 0.04). The 5-year overall survival and disease-free survival were superior in the laparoscopic group (p = 0.03 and p = 0.01, respectively); however, the survival differences were not significant in the subgroup analysis by stage. Laparoscopic gastrectomy had fewer recurrences than open gastrectomy. The pattern of recurrence was not different between the groups. CONCLUSIONS: Laparoscopic gastrectomy can be safely applied in both early and locally advanced gastric cancer without compromising oncologic outcomes. TRIAL REGISTRATION: Retrospective registration.

Adoptive transfer of DMSO-induced regulatory T cells exhibits a similar preventive effect compared to an in vivo DMSO treatment for chemical-induced experimental encapsulating peritoneal sclerosis in mice.

Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). This disease leads to intestinal obstruction with or without peritonitis. The imbalance between the populations of Th17 and regulatory T (Treg) cells (higher Th17 cells and lower Treg cells) is part of the pathogenesis of EPS formation. We demonstrated that dimethyl sulfoxide (DMSO) effectively inhibited autoimmune diabetes recurrence in the islet transplantation of NOD mice via the induction of the differentiation of Treg cells. In this study, we investigated the therapeutic potential of DMSO in the inhibition of EPS formation by a mouse model. Under DMSO treatment, the thickening of the parietal and visceral peritoneum was significantly reduced. The populations of CD4, CD8, and IFN-γ-producing CD4 and CD8 T cells were decreased. The populations of IL-4-producing CD4 T lymphocytes, IL-10-producing CD4 T lymphocytes, CD4 CD69 T lymphocytes and Treg lymphocytes were increased. The expression levels of the cytokines IFN-γ, IL-17a, TNF-α and IL-23, in ascites, were significantly decreased following the DMSO treatment. Furthermore, the differentiation of Treg cells was induced by DMSO from naïve CD4 T cells in vitro, and these cells were adoptively transferred into the EPS mice and significantly prevented EPS formation, exhibiting a comparable effect to the in vivo DMSO treatment. We also demonstrated that the differentiation of Treg cells by DMSO occurred via the activation of STAT5 by its epigenetic effect, without altering the PI3K-AKT-mTOR or Raf-ERK pathways. Our results demonstrated, for the first time, that in vivo DMSO treatment suppresses EPS formation in a mouse model. Furthermore, the adoptive transfer of Treg cells that were differentiated from naïve CD4 T cells by an in vitro DMSO treatment exhibited a similar effect to the in vivo DMSO treatment for the prevention of EPS formation.

A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway.

The pluripotency factor Lin28 blocks the expression of let-7 microRNAs in undifferentiated cells during development, and functions as an oncogene in a subset of cancers. Lin28 binds to let-7 precursor (pre-let-7) RNAs and recruits 3' terminal uridylyl transferases to selectively inhibit let-7 biogenesis. Uridylated pre-let-7 is refractory to processing by Dicer, and is rapidly degraded by an unknown RNase. Here we identify Dis3l2 as the 3'-5' exonuclease responsible for the decay of uridylated pre-let-7 in mouse embryonic stem cells. Biochemical reconstitution assays show that 3' oligouridylation stimulates Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic stem cells leads to the stabilization of pre-let-7. Our study establishes 3' oligouridylation as an RNA decay signal for Dis3l2, and identifies the first physiological RNA substrate of this new exonuclease, which is mutated in the Perlman syndrome of fetal overgrowth and causes a predisposition to Wilms' tumour development.

Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance.

We examined the involvement of adipocyte cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2)-prostaglandin E receptor (EP)3-mediated signaling during hypertrophy and hypoxia in the development of obesity-associated adipose tissue (AT) inflammation and insulin resistance. The experiments were conducted with high-fat diet (HFD)-induced obese rats, db/db mice, human subjects, and 3T3-L1 and the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes; the groups were treated with selective inhibitors of COX-2 [celecoxib 30 mg/kg, half maximal inhibitory concentration (IC50) ≈ 0.04 µM] and EP3 (L-798106 100 µg/kg, IC50 ≈ 0.5 µM) or a short interfering RNA. There were strong, positive correlations between adipocyte COX-2 and EP3 gene expressions and the AT TNF-α and monocyte chemotactic protein-1 contents and the homeostatic model assessment for insulin resistance in HFD-induced obese rats, as well as body mass index in human subjects. Treatment with COX-2 and EP3 inhibitors significantly reversed AT inflammatory gene and protein expressions (-50%) and impaired glucose and insulin tolerance in db/db mice. COX-2 inhibition diminished the chemotaxis of adipocytes isolated from HFD rats to macrophages and T cells. Targeting inhibition of adipocyte COX-2 and EP3 during hypertrophy and hypoxia reversed the release of the augmented proinflammatory adipokines and the diminished adiponectin and also suppressed NF-κB and hypoxia-inducible factor-1α transcription activation. These findings suggest that adipocyte COX-2 PGE2-EP3-mediated signaling is crucially involved in the development of obesity-associated AT inflammation and insulin resistance.-Chan, P.-C., Hsiao, F.-C., Chang, H.-M., Wabitsch, M., Hsieh, P. S. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance.

The co-chaperones Fkbp4/5 control Argonaute2 expression and facilitate RISC assembly.

Argonaute2 (Ago2) protein and associated microRNAs (miRNAs) or small interfering RNAs (siRNAs) form the RNA-induced silencing complex (RISC) for target messenger RNA cleavage and post-transcriptional gene silencing. Although Ago2 is essential for RISC activity, the mechanism of RISC assembly is not well understood, and factors controlling Ago2 protein expression are largely unknown. A role for the Hsc70/Hsp90 chaperone complex in loading small RNA duplexes into the RISC has been demonstrated in cell extracts, and unloaded Ago2 is unstable and degraded by the lysosome in mammalian cells. Here we identify the co-chaperones Fkbp4 and Fkbp5 as Ago2-associated proteins in mouse embryonic stem cells. Pharmacological inhibition of this interaction using FK506 or siRNA-mediated Fkbp4/5 depletion leads to decreased Ago2 protein levels. We find FK506 treatment inhibits, whereas Fkbp4/5 overexpression promotes, miRNA-mediated stabilization of Ago2 expression. Simultaneous treatment with a lysosome inhibitor revealed the accumulation of unloaded Ago2 complexes in FK506-treated cells. We find that, consistent with unloaded miRNAs being unstable, FK506 treatment also affects miRNA abundance, particularly nascent miRNAs. Our results support a role for Fkbp4/5 in RISC assembly.

Dimethyl sulfoxide inhibits spontaneous diabetes and autoimmune recurrence in non-obese diabetic mice by inducing differentiation of regulatory T cells.

Type 1 diabetes mellitus (T1D) is caused by the destruction of insulin-producing ß cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective therapeutic strategy for T1D. However, the survival of islet grafts can be disrupted by recurrent autoimmunity. Dimethyl sulfoxide (DMSO) is a solvent for organic and inorganic substances and an organ-conserving agent used in solid organ transplantations. DMSO also exerts anti-inflammatory, reactive oxygen species scavenger and immunomodulatory effects and therefore exhibits therapeutic potential for the treatment of several human inflammatory diseases. In this study, we investigated the therapeutic potential of DMSO in the inhibition of autoimmunity. We treated an animal model of islet transplantation (NOD mice) with DMSO. The survival of the syngeneic islet grafts was significantly prolonged. The population numbers of CD8, DC and Th1 cells were decreased, and regulatory T (Treg) cell numbers were increased in recipients. The expression levels of IFN-γ and proliferation of T cells were also reduced following DMSO treatment. Furthermore, the differentiation of Treg cells from naive CD4 T cells was significantly increased in the in vitro study. Our results demonstrate for the first time that in vivo DMSO treatment suppresses spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Treg cells.

Lin28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7).

The pluripotency factor Lin28 recruits a 3' terminal uridylyl transferase (TUTase) to selectively block let-7 microRNA biogenesis in undifferentiated cells. Zcchc11 (TUTase4/TUT4) was previously identified as an enzyme responsible for Lin28-mediated pre-let-7 uridylation and control of let-7 expression. Here we investigate the protein and RNA determinants for this interaction. Biochemical dissection and reconstitution assays reveal the TUTase domains necessary and sufficient for Lin28-enhanced pre-let-7 uridylation. A single C2H2-type zinc finger domain of Zcchc11 was found to be responsible for the functional interaction with Lin28. We identify Zcchc6 (TUTase7) as an alternative TUTase that functions with Lin28 in vitro, and accordingly, we find Zcchc11 and Zcchc6 redundantly control let-7 biogenesis in embryonic stem cells. Our study indicates that Lin28 uses two different TUTases to control let-7 expression and has important implications for stem cell biology as well as cancer.

Doxorubicin-loaded Polymeric Biotin-PEG-SeSe-PBLA Micelles with surface Binding of Biotin-Mediated Cancer Cell Targeting and Redox-Responsive Drug release for enhanced anticancer efficacy.

Biotin receptors are overexpressed in various cancer cell types, essential in tumor development, metabolism, and metastasis. Chemotherapeutic agents may be more effective and have fewer adverse effects if they specifically target the biotin receptors on cancer cells. Polymeric micelles (PMs) with nanoscale size via the EPR effect to accumulate near tumor tissue. We utilized the solvent exchange technique to crate polymeric Biotin-PEG-SeSe-PBLA micelles. This underwent self-assembly to create uniformly dispersed PMs with a hydrodynamic diameter of 81.54 ± 0.23 nm. The resulting PMs characterized by 1HNMR, 13CNMR, FTIR, and Raman spectroscopy. PMs exhibited a high efficacy of Doxorubicin encapsulation (EE) and loading content (DLC), with values of 5.93 wt% and 74.32 %, respectively. DOX@Biotin-PEG-SeSe-PBLA micelles showed optimal DOX release, around 89 % and 74 % in 10 mM glutathione and 0.1 % H2O2, respectively, within 72 hours, in the simulated cancer redox pool. Fascinatingly, the blank Biotin-PEG-SeSe-PBLA micelles did not affect the HaCaT or HeLa cell lines; approximately 85 % of the cells were metabolically active. Contrarily, at a 5 µg/ml concentration, DOX@Biotin-PEG-SeSe-PBLA specifically inhibited the proliferation of roughly 76 % of HeLa cells and 11 % of HaCaT cells. The fluorescence microscopy results demonstrated that biotin-decorated micelles were more successfully internalized by HeLa cells, which overexpress the biotin receptor, than by non-targeted micelles in vitro. In summary, the diselenide-linked Biotin-PEGSeSe-PBLA formed smart PMs that could offer DOX specific to cancer cells with precision and are physiologically durable.

Focusing of surface plasmon polaritons propagating at the SiO2/Ag interface with 2-level and 4-level Fresnel phase zone pad structures.

We propose and demonstrate dielectric Fresnel phase zone pad (FPZP) structures for focusing surface plasmon polaritons (SPPs) propagating at the SiO2/Ag interfaces. We exploited up-conversion fluorescence microscopy to characterize the SPP focusing. We first report on the SPP focusing with 2-level FPZP structures that introduced a π-phase shift in the SPP wavefront between adjacent zones. We optimized the SPP focusing by fine-tuning the longitudinal width of the FPZP structure. This led to the enhancement of the peak intensity of the SPP focal spot and the reduction of the focal spot size in both the longitudinal and transverse directions. Such focusing was also demonstrated with different focal lengths. To further improve the SPP focusing, we developed a 4-level FPZP structure, which introduced a π/2-phase shift in the SPP wavefront between adjacent zones. With the optimized 4-level FPZP structure, the SPP focal spot peak intensity is further improved, and the spot size is reduced. To assist the design of the FPZP structures, we carried out theoretical analysis and numerical calculations to determine the SPP wavelengths at various oxide/Ag interfaces. We also carried out finite difference time domain (FDTD) calculations to simulate the SPP focusing with the FPZP structures. The results of the FDTD simulation agree with the experimental results qualitatively.

Association of Coracoacromial Ligament Degeneration With Rotator Cuff Tear Patterns and Retear Rate.

Background: Coracoacromial ligament (CAL) degeneration is thought to be a factor in external impingement in bursal-sided rotator cuff tears, but CAL release is associated with adverse effects. Purpose: To investigate the association between CAL degeneration and the patterns of massive rotator cuff tears using multiple modalities and to assess the effect of CAL degeneration on supraspinatus tendon retear rates. Study Design: Cohort study; Level of evidence, 2. Methods: The authors prospectively recruited 44 patients who had undergone arthroscopic rotator cuff repair without acromioplasty or CAL release. Preoperative radiographs and magnetic resonance imaging (MRI) scans were reviewed to determine acromial morphology and CAL thickness, respectively. Rotator cuff tears were categorized as isolated supraspinatus or massive (involvement of ≥2 tendons), with massive tears categorized using the Collin classification. Acromial degeneration was analyzed using the Copeland-Levy classification. The CAL was biopsied intraoperatively and histologically analyzed using the Bonar score. At 6-month follow-up, the integrity of the repaired supraspinatus tendon was analyzed on MRI using the Sugaya classification. Finally, the associations among CAL degeneration, rotator cuff tear pattern, and arthroscopic grading were investigated. Results: Patients with Collin type B rotator cuff tear had significantly higher CAL Bonar scores than those with Collin type A or isolated supraspinatus tears (10.0 vs 6.8 and 3.4; P = .03 and P < .001, respectively). Patients with a degenerative acromial undersurface of Copeland-Levy stage 2 or 3 had CALs with significantly higher Bonar scores than those with an intact acromial undersurface (8.4 and 8.2 vs 3.5; P = .034 and P = .027, respectively). The CAL Bonar scores of patients with different stages of the 6-month postoperative Sugaya classification were comparable (6.5, 7.2, 8.0, and 7.8 for stages 1, 2, 3, and 4, respectively; P = .751). Conclusion: CAL degeneration was more severe in anterosuperior-type massive rotator cuff tears. Interestingly, even without acromioplasty, the severity of CAL degeneration did not affect the retear rate of the supraspinatus tendon.

Derivation and Preclinical Characterization of CYT-303, a Novel NKp46-NK Cell Engager Targeting GPC3.

Glypican-3 (GPC3) is an oncofetal antigen that is highly expressed in multiple solid tumors, including hepatocellular carcinoma, and is barely expressed in adult normal tissues except the placenta. NKp46 activation receptor is expressed in all-natural killer (NK) cells, including tumor-infiltrating NK cells. FLEX-NKTM is a platform for the production of tetravalent multifunctional antibody NK cell engagers (NKE). CYT-303 was designed using the FLEX-NK scaffold, incorporating a novel humanized NKp46 binder that does not induce NKp46 internalization and a humanized GPC3 binder that targets the membrane-proximal lobe to mediate NK cell-redirected killing of HCC tumors. CYT-303 shows sub-nanomolar binding affinities to both GPC3 and NKp46. CYT-303 was highly potent and effective in mediating NK cell-redirected cytotoxicity against multiple HCC tumor cell lines and tumor spheroids. More interestingly, it can reverse the dysfunction induced in NK cells following repeated rounds of serial killing of tumors. It also mediated antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity against GPC3-expressing HCC tumors. In vivo, CYT-303 showed no toxicity or cytokine release in cynomolgus monkeys up to the highest dose (60 mg/kg), administered weekly by intravenous infusion for 28 days. These results demonstrate the potential of CYT-303 to be a safe and effective therapy against HCC.

Poly(vinylidene fluoride) Intestinal Sleeve Implants for the Treatment of Obesity and Type 2 Diabetes.

Currently, treatment of diabetes and associated obesity involves Roux-en-Y gastric bypass or sleeve gastrectomy to reduce the absorption of nutrients from the intestine to achieve blood glucose control. However, the surgical procedure and subsequent recovery are physically and psychologically burdensome for patients, with possible side effects, so alternative treatments are being developed. In this study, two methods, solution casting and machine direction orientation (MDO), were used to prepare intestinal implants made of poly(vinylidene fluoride) (PVDF) film and implant them into the duodenum of type 2 diabetic rats for the treatment of obesity and blood glucose control. The PVDF film obtained by the MDO process was characterized by FT-IR, Raman spectroscopy, XRD and piezoelectricity tests, which showed higher composition of ß crystalline phase and better elongation and mechanical strength in specific directions. Therefore, the material was finally tested on rats after it was proven to be non-toxic by biological toxicity tests. The PVDF was implanted into alloxan-induced diabetic rats, which were used as a model of impaired insulin secretion due to pancreatic beta cell destruction rather than obesity-induced diabetes, and rats were tracked for 24 days, showing significantly improved body weight and blood glucose levels. As an alternative therapeutic option, intestinal sleeve implant showed future potential for application.

Does Weaver-Dunn procedure have a role in chronic acromioclavicular dislocations? A meta-analysis.

BACKGROUND: In treatment of chronic acromioclavicular (AC) joint dislocations, both the Weaver-Dunn procedure (WD) and CC ligament reconstruction (CCR) are recommended options due to the low possibility of healing of the coracoclavicular (CC) ligaments. The aim of this review was to determine whether CCR will yield favorable clinical and radiographic outcomes in the treatment of chronic AC dislocations. METHOD: The Cochrane Library, EMBASE, and PubMed databases were searched for literature on chronic AC dislocations from data inception to June 30, 2021. Patient data were pooled using standard meta-analytic approaches. The Cochrane-Mantel-Haenszel method and variance-weighted means were used to analyze the outcomes. The Review Manager version 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used to calculate the heterogenicity, mean difference, and relative risk (RR) for all outcomes in the meta-analysis. RESULTS: The current analysis included four trials on this topic, and all AC joint dislocations were classified as Rockwood types III to VI. The pooled data showed that the CCR group had significantly better post-operative American Shoulder and Elbow Surgeons Shoulder (ASES) scores, Oxford Shoulder Scores (OSSs), and Nottingham Clavicle Scores (NCSs) than the WD group, with a significant difference (p < 0.001, p = 0.020, and p < 0.001, respectively). In terms of the post-operative Constant-Murley Scores (CMSs), there were no significant differences between the CCR group and the WD group (p = 0.100). The CCR group had significantly better post-operative abduction and flexion of the index shoulder than the WD group (p < 0.001 and p < 0.001, respectively). In terms of radiological outcomes, the post-operative coracoclavicular distance (CCD) with a 10 kg load was smaller in the CCR group compared to that in the WD group (p < 0.001). The overall surgical wound infection rate was 11.6% in the WD group and 12.9% in the CCR, respectively (p = 0.82). CONCLUSION: The CCR group had better clinical outcome scores in the ASES, OOS, NCS, abduction, flexion, and external rotation than the WD group. In terms of radiological outcomes, the CCR group showed less displacement in weight-loaded post-CCD than the WD group, which indicated that the CCR provided more stability and resistance to deformation forces.

Comparison of Biomechanical Failure Loads Between Tape-Type and Conventional Sutures in Internal Knotless Anchor-Based Constructs.

Background: Despite the increasing prevalence of tape-type sutures, whether internal knotless anchors can consistently affix tape-type sutures has not been thoroughly investigated. Purpose: To evaluate whether substituting tape-type sutures for conventional sutures influences the suture-holding strength of internal knotless anchors. Study Design: Controlled laboratory study. Level of evidence, 5. Methods: A total of 3 internal knotless anchors were tested: a spiral core clamping anchor (Footprint Ultra PK), a winged clamping anchor (PopLok), and a spooling anchor (ReelX STT). Four constructs were compared for each type of anchor, with the anchor double or quadruple loaded with tape-type sutures or conventional sutures. The testing protocol comprised preloading suture tension to 10 N; cyclic loading, in which tension increased in increments of 10 N from 10 to 90 N; and a load-to-failure stage set at a speed of 0.5 mm/s. The clinical failure load (CFL) was defined as suture slippage of ≥3 mm. Also, 1-way analysis of variance and power analysis were used to compare the CFLs of the constructs. Results: For the quadruple-loaded spiral core clamping anchors, a significant reduction in CFLs was seen with conventional sutures over tape-type sutures (138.10 ± 4.73 vs 80.00 ± 12.25 N, respectively; P < .001). This reduction was not observed under the double-loaded condition (conventional vs tape type: 76.00 ± 5.48 vs 80.00 ± 10.00 N, respectively). Substitution of the suture materials did not significantly reduce the CFLs for the winged clamping anchors (conventional vs tape type: 40.00 ± 10.00 vs 30.00 ± 7.07 N for double loaded, respectively, and 64.00 ± 13.41 vs 50.00 ± 10.00 N for quadruple loaded, respectively) or the spooling anchors (conventional vs tape type: 62.00 ± 19.23 vs 56.32 ± 20.20N for double loaded, respectively, and 72.00 ± 21.68 vs 84.00 ± 13.42 N for quadruple loaded, respectively). Conclusion: Substituting tape-type sutures for conventional sutures increased the CFLs of some internal knotless anchors. With specific suture-anchor combinations, quadruple-loaded conventional suture anchors had CFLs higher than those of double-loaded conventional suture anchors. Clinical Relevance: When multiple tape-type sutures are used in conjunction with a clamping anchor, clinicians should note a possible reduction in CFLs and resultant early suture slippage.